Substituted 2-Aminoacetamides and the Use Thereof

ABSTRACT

The invention is directed to substituted 2-aminoacetamides represented by formula (II): 
     
       
         
         
             
             
         
       
     
     and to pharmaceutically acceptable salts and prodrugs thereof, wherein the substituents are defined herein. The invention is also directed to the use of substituted 2-aminoacetamides in methods for the treatment of neuronal damage following global and focal ischemia, and for the treatment, prevention or amelioration of pain, anxiety, or manic depression, as anticonvulsants, as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to substituted 2-aminoacetamides and the discoverythat these compounds act as blockers of sodium (Na⁺) channels.

2. Related Background Art

Several classes of therapeutically useful drugs, including localanesthetics such as lidocaine and bupivacaine, antiarrhythmics such aspropafenone and amioclarone, and anticonvulsants such as lamotrigine,phenyloin and carbamazepine, have been shown to share a common mechanismof action by blocking or modulating Na⁺ channel activity (Catterall, W.A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents isbelieved to act by interfering with the rapid influx of Na⁺ ions.

Recently, other Na⁺ channel blockers such as BW619C89 and lifarizinehave been shown to be neuroprotective in animal models of global andfocal ischemia and are presently in clinical trials (Graham et al., J.Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J.Pharmacol. 115:1425-1432 (1995); SCRIP 1870:8 (1993); SCRIP 1773:14(1992)).

The neuroprotective activity of Na⁺ channel blockers is due to theireffectiveness in decreasing extracellular glutamate concentration duringischemia by inhibiting the release of this excitotoxic amino acidneurotransmitter. Studies have shown that unlike glutamate receptorantagonists, Na⁺ channel blockers prevent hypoxic damage to mammalianwhite matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, theymay offer advantages for treating certain types of strokes or neuronaltrauma where damage to white matter tracts is prominent.

Another example of clinical use of a Na⁺ channel blocker is riluzole.This drug has been shown to prolong survival in a subset of patientswith ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and hassubsequently been approved by the FDA for the treatment of ALS. Inaddition to the above-mentioned clinical uses, carbamazepine, lidocaineand phenyloin are occasionally used to treat neuropathic pain, such asfrom trigeminal neurologia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)),and carbamazepine and lamotrigine have been used for the treatment ofmanic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76(1994)).

It has been established that there are at least five to six sites on thevoltage-sensitive Na⁺ channels which bind neurotoxins specifically(Catterall, W. A., Science 242:50-61 (1988)). Studies have furtherrevealed that therapeutic antiarrhythmics, anticonvulsants and localanesthetics whose actions are mediated by Na⁺ channels, exert theiraction by interacting with the intracellular side of the Na⁺ channel andallosterically inhibiting interaction with neurotoxin receptor site 2(Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)).

PCT International Published Application WO 90/14334 and WO 97/05102disclose 2-(4-substituted)-benzylamino-2-methyl-propanamide derivativesrepresented by Formula I:

where n is 0-3; X is O, S, CH₂ or NH; each of R and R₁ independently ishydrogen, C₁₋₆ alkyl, halogen, hydroxy, C₁₋₄ alkoxy, or trifluoromethyl;each of R₂, R₃ and R₄ independently is hydrogen, C₁₋₆ alkyl or C₃₋₇cycloalkyl. The compounds are disclosed to be useful as antiepileptics,in the treatment of Parkinson's disease and as neuroprotective agents,e.g. preventing or treating neuronal loss associated with stroke,hypoxia, ischemia, CNS trauma, hypoglycemia or surgery, and in treatingand preventing neurodegenerative diseases such as Alzheimer's disease,amyotrophic lateral sclerosis, Down's syndrome, Huntington's disease,dementia caused by acquired immunodeficiency syndrome (AIDS), infarctualdementia and infections or inflammations in the brain; they can also beused as antidepressants, hypnotics, and antispastic agents and intreating ocular damage and retinopathy. However, their mechanism ofaction was not disclosed.

SUMMARY OF THE INVENTION

The present invention is related to treating a disorder responsive tothe blockade of sodium channels in a mammal suffering from excessactivity of said channels by administering an effective amount of acompound of Formula I. The present invention is also related to treatinga disorder responsive to the blockade of sodium channels in a mammalsuffering therefrom by administering an effective amount of a compoundof Formula II as described herein.

The present invention is also directed to the use of a compound ofFormulae I or II for the treatment of neuronal damage following globaland focal ischemia, and for the treatment or prevention ofneurodegenerative conditions such as amyotrophic lateral sclerosis(ALS), as antimanic depressants, as local anesthetics, asantiarrhythmics and for the treatment or prevention of diabeticneuropathy and for the treatment of pain including chronic pain.

The present invention also is directed to the process for preparingnovel substituted 2-aminoacetamide of Formula II.

A first aspect of the present invention is directed to the use ofcompounds of Formulae I or II as blockers of sodium channels.

A second aspect of the present invention is to provide a method fortreating, preventing or ameliorating neuronal loss following global andfocal ischemia; treating, preventing or ameliorating pain includingchronic pain; treating, preventing or ameliorating neurodegenerativeconditions; treating, preventing or ameliorating manic depression;inducing local anesthesia; and treating arrhythmias by administering acompound of Formulae I or II to a mammal in need of such treatment.

A number of compounds within the scope of the present invention arenovel compounds. Therefore, a third aspect of the present invention isto provide novel compounds of Formula II, and to also provide for theuse of these novel compounds for treating, preventing or amelioratingconvulsions.

A fourth aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the blockade ofsodium ion channels, containing an effective amount of a compound ofFormulae I or II in a mixture with one or more pharmaceuticallyacceptable carriers or diluents.

A fifth aspect of the present invention is directed to methods forpreparing novel compounds of Formulae II.

DETAILED DESCRIPTION OF THE INVENTION

The present invention arises out of the discovery that compounds ofFormulae I and II act as blocker of the Na⁺ channel. In view of thisdiscovery, compounds of Formulae I and II are useful for treatingdisorders responsive to the blockade of sodium ion channels.

The compounds useful in this aspect of the present invention aresubstituted 2-aminoacetamides represented by Formula II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁ R₂, R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl orcarboxyalkyl;

R₅, R₆ and R₇ are independently hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl orcarboxyalkyl, or R₅, is defined as above, and R₆ and R₇ together withthe nitrogen atom to which they are attached form a heterocycle;

A₁ and A₂ are independently aryl, heteroaryl, saturated or partiallyunsaturated carbocycle or saturated or partially unsaturatedheterocycle, any of which is optionally substituted;

X is one or O, S, NR₈, CH₂, C(O), NR₈C(O), C(O)NR₈SO, SO₂ or a covalentbond; where

R₈ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;

n is 0, 1, 2 or 3.

Preferred compounds falling within the scope of Formula II includecompounds wherein A₁ and A₂ are both aryl moieties, preferably bothphenyl moieties, that are each optionally independently substituted byone or two substituents independently selected from the group consistingof halogen, nitro, amino, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, cyano, C₁₋₆alkoxy or C₆₋₁₀ aryloxy; R₁ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl orC₆₋₁₀ aryl; O or S.

Preferred compounds within Formula II also include those compounds whereA₁ is an optionally substituted aryl group selected from the groupconsisting of phenyl and naphthyl, and A₂ is an optionally substitutedheteroaryl or aryl group selected from the group consisting of pyridyl,pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl,3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl, biphenylmethyl, triphenylmethyl and quinoxalinyl.

Additional preferred compounds within Formula II also include thosecompounds where A₁ is an optionally substituted aryl group selected fromthe group consisting of phenyl or naphthyl, and A₂ is an optionallysubstituted carbocycle or heterocycle selected from the group consistingof cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl,adamantyl, exo-norbornyl and cyclopentenyl.

Additional preferred compounds within Formula II include those compoundswhere A₁ is an optionally substituted heteroaryl or aryl group selectedfrom the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl,naphthyl, quinolyl, furanyl, and thiophenyl, and A₂ is an optionallysubstituted heteroaryl or aryl group selected from the group consistingof phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl.

Additional preferred compounds within Formula II include those compoundswhere A₁ is an optionally substituted, saturated or partiallyunsaturated carbocycle or heterocycle selected from the group consistingof cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, piperidinyl,pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl, and A₂ is anoptionally substituted aryl or heteroaryl group selected from the groupconsisting of phenyl, furanyl, thiophenyl, quinolinyl,3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl, or naphthyl.

Exemplary preferred compounds that may be employed in this method ofinvention include, without limitation:

-   2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide;-   2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;-   2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(2-adamantanoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;-   2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;-   2-(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(exo-2-norbornoxy)benzylamino)-2-methyl-propanamide;-   2-(3-(4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide;-   2-(4-(4-pyridinoxy)benzylamino)-2-methyl-propanamide;-   2-(3-fluoro-4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide;-   2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;-   2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide; and-   2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.

Since the compounds of Formula I and II are blockers of sodium (Na⁺)channels, a number of diseases and conditions mediated by sodium ioninflux can be treated employing these compounds. Therefore, theinvention is related to a method of treating, preventing or amelioratingneuronal loss associated with stroke, global and focal ischemia, CNStrauma, hypoglycemia and surgery, spinal cord trauma; as well astreating or ameliorating neurodegenerative diseases includingAlzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease,treating or ameliorating anxiety, convulsions, glaucoma, migraineheadache, and muscle spasm. The compounds of Formula I and II are alsouseful as antimanic depressants, as local anesthetics, and asantiarrhythmics; as well as for treating, preventing or amelioratingpain including surgical, chronic and neuropathic pain. In each instance,the methods of the present invention require administering to an animalin need of such treatment an effective amount of a sodium channelblocker of the present invention, or a pharmaceutically acceptable saltor prodrug thereof.

The present invention is also directed to novel compounds within thescope of Formula II. These compounds include those compounds of FormulaII where:

R₁, R₂, R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkylor carboxyalkyl;

R₅, R₆ and R₇ are independently hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl orcarboxyalkyl, or R₅, is defined as above, and R₆ and R₇ together withthe nitrogen atom to which they are attached form a heterocycle,including piperidine, piperazine, morpholine;

A₁ and A₂ are independently aryl, heteroaryl, saturated or partiallyunsaturated carbocycle or saturated or partially unsaturatedheterocycle, any of which is optionally substituted;

X is one or O, S, NR₈, CH₂, C(O), NR₈C(O), C(O)NR₈, SO, SO₂ or acovalent bond; where

R₈ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;

n is 0, 1, 2 or 3.

provided that:

when X is O, S, CH₃ or NH; R₁ and R₂ are hydrogen, R₃ and R₄ are methyl,then A₁ and A₂ are not both phenyl, with A₂ optionally substituted byone or two non-hydrogen substituents.

Specifically, preferred substituted 2-aminoacetamides are represented byFormulae III-VIII. In particular, a preferred embodiment is representedby Formulae III and IV:

or a pharmaceutically acceptable salt or prodrug thereof, wherein R₁,R₂, R₃, R₄, R₅, R₆, R₇, X, n, A₁ and A₂ are as defined previously withrespect to Formula II; and

R₉, R₁₀, R₁₁ and R₁₂ independently are hydrogen, halo, haloalkyl, aryl,cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl,alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl,heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl,nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido,alkoxy, carboxy, carbonylamido or alkylthiol; or

R₉ and R₁₀ or R₁₁ and R₁₂ are taken together with the carbon atoms towhich they are attached to form a carbocycle or heterocycle. Examples ofbridges formed by R₉ and R₁₀ or R₁₁ and R₁₂ taken together are —OCH₂O—,—OCF₂O—, —(CH₂)₃—, —(CH₂)₄—, —OCH₂CH₂O—, CH₂N(R₁₈)CH₂—,—CH₂CH₂N(R₁₈)CH₂—, —CH₂N(R₁₈)CH₂CH₂— and —CH═CH—CH═CH—;where R₁₈ is hydrogen, alkyl or cycloalkyl;provided that when A₂ in Formula III is an optionally substitutedphenyl, then R₉ and R₁₀ or R₁₁ and R₁₂ are taken together with thecarbon atoms to which they are attached to form a carbocycle orheterocycle.R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ independently are hydrogen, halo, haloalkyl,aryl, cycloalkyl, saturated or partially unsaturated heterocycle,heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl,carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido,hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido oralkylthiol; or

one of R₁₃ and R₁₄, or R₁₄ and R₁₅, or R₁₅ and R₁₆, or R₁₆ and R₁₇ aretaken together with the carbon atoms to which they are attached to forma carbocycle or heterocycle. Examples of bridges formed by R₁₃ and R₁₄,or R₁₄ and R₁₅, or R₁₅ and R₁₆, or R₁₆ and R₁₇ taken together are—OCH₂O—, —OCF₂O—, —(CH₂)₃—, —(CH₂)₄—, —OCH₂CH₂O—, —CH₂N(R₁₈)CH₂—,—CH₂CH₂N(R₁₈)CH₂—, —CH₂N(R₁₈)CH₂CH₂— and —CH═CH—CH═CH—; where R₁₈ ishydrogen, alkyl or cycloalkyl.

provided that when A₁ in Formula IV is an optionally substituted phenyl,then R₁₃ and R₁₄, or R₁₄ and R₁₅, or R₁₅ and R₁₆, or R₁₆ and R₁₇ aretaken together with the carbon atoms to which they are attached to forma carbocycle or heterocycle.

Preferred values of A₂ in Formula III include furanyl, thiophenyl,quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl, and naphthyl.

Preferred values of A₁ in Formula IV include furanyl, thiophenyl,quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl,tetrahydronaphthyl and naphthyl.

Another preferred embodiment of the invention includes substituted2-aminoacetamides represented by Formula V and Formula VI:

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R₁-R₇, R₉-R₁₂, R₁₃-R₁₇, n and X are as defined previously with respectto Formulae II, III and IV; and

A, B, C, D and E are independently nitrogen or carbon, provided that nomore than three of A, B, C, D and E are nitrogen, and there is nosubstituent, except for oxygen (when the nitrogen is present as aN-oxide), present on A, B, C, D or E when said A, B, C, D or Erepresents nitrogen.

Preferred compounds of Formula V are those where one, two or three of Athrough E are nitrogens. Preferred compounds of Formula VI are thosewhere one or two of A through D are nitrogens.

Another preferred embodiment of the invention includes substituted2-aminoacetamide represented by Formula VII and Formula VIII:

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R₁-R₇, R₉-R₁₂, R₁₃-R₁₇, n and X are as defined previously with respectto Formulae II, III and IV; and

B₁ is an optionally substituted, saturated or partially unsaturatedcarbocycle or optionally substituted, saturated or partially unsaturatedheterocycle; and

B₂ is an optionally substituted, saturated or partially unsaturatedcarbocycle or optionally substituted, saturated or partially unsaturatedheterocycle.

Preferred B₁ and B₂ independently include cyclopentyl, cyclohexyl,cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl andpiperidinyl.

Generally, preferred compounds of Formulae II-VIII are those compoundswhere R₁ and R₂ is hydrogen or alkyl, more preferably hydrogen, methylor ethyl, and where R₃ and R₄ are independently hydrogen or C₁₋₄ alkyl.

Preferred values of X in Formulae II-VIII are O and S.

Preferred values of R₅-R₇ with respect to Formulae II-VIII are hydrogenor C₁₋₄ alkyl.

Preferred values of R₉-R₁₂, and R₁₃-R₁₇, with respect to FormulaeII-VIII include hydrogen, halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl,C₁-C₆ hydroxyalkyl, nitro, amino, ureido, cyano, C₁-C₆ acylamido,hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy, and carboxy.Alternatively, R₉ and R₁₀ or R₁₁ and R₁₂, or two adjacent R₁₃ throughR₁₇ can form a bridge selected from the group consisting of —OCH₂O—,—(CH₂)₃—, —(CH₂)₄—, —OCH₂CH₂O—, —CH₂N(R₁₈)CH₂—, —CH₂CH₂N(R₁₈)CH₂—,—CH₂N(R₁₈)CH₂CH₂—, and CH═CH—CH═CH—, where R₁₈ is hydrogen or C₁-C₆alkyl. Most preferably, at least one, two or three of R₉, R₁₀, R₁₁, R₁₂are hydrogen. Most preferably, at least one, two or three of R₁₃ throughR₁₇ are hydrogen.

With respect to the novel methods of treatment of the present invention,an additional preferred subset of substituted 2-aminoacetamide compoundsincludes compounds of Formula II, wherein A₁ and A₂ are phenyl moieties,that A₂ is substituted by one or two substituents independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, halogen, hydroxy,C₁₋₄ alkoxy, or trifluoromethyl; each of R₁ and R₂ are hydrogen; R₃ andR₄ are methyl; and R₅-R₇ are independently C₁₋₆ alkyl or C₃₋₇cycloalkyl.

Useful compounds in this aspect of the present invention include:

-   2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide;-   2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;-   2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(2-adamantanoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;-   2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;-   2-(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(exo-2-norbornoxy)benzylamino)-2-methyl-propanamide;-   2-(3-(4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide;-   2-(4-(4-pyridinoxy)benzylamino)-2-methyl-propanamide;-   2-(3-fluoro-4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide;-   2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;-   2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;-   2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide; and-   2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Useful cycloalkyl groups include C₃₋₈ cycloalkyl groups. Typicalcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl and cycloheptyl.

Useful saturated or partially saturated carbocyclic groups arecycloalkyl groups as defined above, as well as cycloalkenyl groups, suchas cyclopentenyl, cycloheptenyl and cyclooctenyl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups include straight-chained and branched C₁₋₁₀ alkylgroups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylenegroup substituted on two adjoining positions on the benzene ring of thecompounds of the invention.

Useful alkenyl groups include C₂₋₆ alkenyl groups, preferably C₂₋₄alkenyl. Typical C₂₋₄ alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, and sec.-butenyl.

Useful alkynyl groups include C₂₋₆ alkynyl groups, preferably C₂₋₄alkynyl. Typical C₂₋₄ alkynyl groups include ethynyl, propynyl, butynyl,and 2-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned C₆₋₁₄ aryl groups.Typical groups include benzyl, phenethyl and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned alkenylgroups substituted by any of the above-mentioned C₆₋₁₄ aryl groups.

Useful arylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups. Typical groups include phenylethynyl and phenylpropynyl.

Useful cycloalkylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned cycloalkylgroups.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl andtrichloromethyl groups.

Useful hydroxyalkyl groups include C₁₋₁₀ alkyl groups substituted byhydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful alkylthio groups include sulphur substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful acylamino groups are any C₁₋₆ acyl (alkanoyl) attached to anamino nitrogen, e.g. acetamido, propionamido, butanoylamido,pentanoylamido, hexanoylamido as well as aryl-substituted C₂₋₆substituted acyl groups.

Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy,hexanoyloxy and the like.

Useful saturated or partially saturated heterocyclic groups includetetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinylgroups.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups.

Useful heteroaryl groups include any one of the following: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl,naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, 5aH-carbazolyl,carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl,furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione,7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one,1,2-benzoisoxazol-3-yl, 4-nitrobenzofurazan, benzimidazolyl, 2-oxindolyland 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogenatom in a ring, such nitrogen atom may be in the form of an N-oxide,e.g. a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and thelike.

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful heteroarylalkenyl groups include any of the above-mentioned C₂₋₄alkenyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful heteroarylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful amino groups include —NH, —NHR₁₉, and —NHR₁₉R₂₀, wherein R₁₉ andR₂₀ are C₁₋₁₀ alkyl or cycloalkyl groups as defined above.

Useful aminocarbonyl groups are carbonyl groups substituted by —NH₂,—NHR₁₉, and —NR₁₉R₂₀, wherein R₁₉ and R₂₀ are C₁₋₁₀ alkyl groups.

Optional substituents on any of the aryl, heterocyclic, heteroaryl, andcycloalkyl rings in Formulae II-VIII include any one of halo, haloalkyl,aryl, heterocycle, cycloalkyl, heteroaryl, alkyl, alkenyl, alkynyl,arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl,aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano,acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy,aminocarbonyl, and alkylthiol groups mentioned above. Preferred optionalsubstituents include: halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro,alkyl, alkoxy and amino.

Certain of the compounds of Formula II may exist as optical isomers andthe invention includes both the racemic mixtures of such optical isomersas well as the individual enantiomers that may be separated according tomethods that are well known to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as hydrochloride, hydrobromide,phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate,mandelate, acetic acid, dichloroacetic acid and oxalate.

Examples of prodrugs include esters or amides of Formula II with R₁-R₇as hydroxyalkyl or aminoalkyl, and these may be prepared by reactingsuch compounds with anhydrides such as succinic anhydride.

The invention is also directed to a method for treating disordersresponsive to the blockade of sodium channels in animals sufferingthereof. Particular preferred embodiments of the substituted2-aminoacetamide for use in method of this invention are represented bypreviously defined Formula II.

The compounds of this invention may be prepared using methods known tothose skilled in the art, or by the novel methods of this invention. Themethods described in PCT published application WO97/05102, can beemployed to synthesize compounds within the scope of the invention.

Compounds with Formulae II-VIII can be prepared as illustrated byexemplary reactions in Schemes 1-5.

The compounds of the present invention were assessed byelectrophysiological assays in dissociated hippocampal neurons forsodium channel blocker activity. These compounds also could be assayedfor binding to the neuronal voltage-dependent sodium channel using ratforebrain membranes and [³H]BTX-B.

Sodium channels are large transmembrane proteins that are expressed invarious tissues. They are voltage sensitive channels and are responsiblefor the rapid increase of Na⁺ permeability in response to depolarizationassociated with the action potential in many excitable cells includingmuscle, nerve and cardiac cells.

One aspect of the present invention is the discovery of the mechanism ofaction of the compounds herein described as specific Na⁺ channelblockers. In one aspect of the present invention it has been discoveredthat compounds disclosed in international published application WO97/05102 are specific Na⁺ channel blockers. Based upon the discovery ofthis mechanism, these compounds, as well as novel compounds describedherein, are contemplated to be useful in treating or preventing neuronalloss due to focal or global ischemia, and in treating or preventingneurodegenerative disorders including ALS, anxiety, and epilepsy. Theyare also expected to be effective in treating, preventing orameliorating neuropathic pain, surgical pain and chronic pain. Thecompounds are also expected to be useful as antiarrhythmics, anestheticsand antimanic depressants.

The present invention is directed to compounds of Formulae II that areblockers of voltage-sensitive sodium channels. According to the presentinvention, those compounds having preferred sodium channel blockingproperties exhibit an IC₅₀ of about 100 μM or less in theelectrophysiological assay described herein. Preferably, the compoundsof the present invention exhibit an IC₅₀ of 10 μM or less. Mostpreferably, the compounds of the present invention exhibit an IC₅₀ ofabout 1.0 μM or less. Substituted 2-aminoacetamide disclosed in WO97/05102, as well as novel compounds of the present invention, may betested for their Na⁺ channel blocking activity by the followingelectrophysiological and binding assays.

Electrophysiological Assay:

Cell preparation: Acute cultures of rat hippocampal neurons wereprepared daily using a modification of procedures described previously(Kuo and Bean, Mol. Pharm. 46:716-725 (1994)). Briefly, hippocampi wereisolated from 3-11 day old rat pup brains (Sprague-Dawley; CharlesRiver) and were sectioned, by hand, into 0.5-1 mm thick transverseslices (Whittemore and Koerner, Eur. J. Pharm. 192:435-438 (1991)).Slices were incubated for at least 30 min at room temperature (20-24°C.) in an oxygenated medium (124 mM NaCl, 3.3 mM KCl, 2.4 mM MgSO₄, 2.5mM CaCl₂, 1.2 mM KH₂PO₄, 26 mM NaHCO₃, pH=7.4) continuously bubbled with5% CO₂/95% O₂. Prior to recording, 4-5 slices were transferred to anoxygenated dissociation medium (82 mM NaSO₄, 30 mM K₂SO₄, 3 mM MgCl₂, 2mM HEPES, 26 mM NaHCO₃, 0.001% phenol red, pH=7.4) containing 3 mg/mLprotease XXIII (Sigma, St. Louis, Mo.) and incubated for 10-15 min at37° C., while continuously bubbling with 5% CO₂/95% O₂. Enzymaticdigestion was terminated by transferring the slices to dissociationmedium without bicarbonate, supplemented with 1 mg/mL bovine serumalbumin and 1 mg/mL trypsin inhibitor (Sigma, St. Louis, Mo.). Sliceswere then transferred to a 35 mm culture dish containing dissociationmedium without bicarbonate, and triturized with a fire-polished glassPasteur pipette to release single cells. Cells were allowed to settle inthis dish for ˜30 minutes and were then used for making electricalrecordings.

Patch-clamp recordings of voltage-sensitive Na⁺ currents: Whole-cellvoltage-clamp recordings were made using conventional patch-clamptechnique (Hamill et al., Pfluegers Arch. 391:85-100 (1981)) with anAxopatch 200A amplifier (Axon Instruments, Foster City, Calif.).Recordings were made within 2-3 hours after neuron dissociation. Therecording chamber was continuously superfused with Tyrode's solution(156 mM NaCl, 3.5 mM KCl, 2 mM CaCl₂, 5 mM NaHCO₃, 10 mM HEPES, 10 mMglucose, pH 7.4) at a speed of about 1 ml/min. Thin-walled pipettes werepulled from 100-μl Clay Adams Accu-Fill 90 Micropet disposable pipettes(Becton, Dickenson and Company, Parsipanny, N.J.), fire-polished andsylgarded (Dow-Corning, Midland, Mich.). The pipette resistances rangedfrom 1 to 3 MΩ when the pipettes were filled with internal solutioncontaining (in mM): 130 CsF, 20 NaCl, 1 CaCl₂, 2 MgCl₂, 10 EGTA, 10HEPES, pH adjusted to 7.4 with CsOH. Drugs and intervening wash-outswere applied through a linear array of flow pipes (Drummond Microcaps,2-μl, 64-mm length). Compounds are dissolved in dimethylsulfoxide (DMSO)to make a 10 mM stock solution, which was subsequently diluted intoTyrode's solution to give final concentrations of 0.1-20 μM. At thehighest (1%) concentration, DMSO inhibited the size of Na⁺ current onlyslightly. Currents were recorded at room temperature (22-25° C.),filtered at 5 kHz with 4-pole Bessel filter, digitized at 20-50-μsintervals, and stored using Digidata 1200 analog/digital interface withPclamp6/Clampex software (Axon Instruments). Residual series resistanceranged from 0.4 to 0.8 MΩ after partial compensation (typically ˜90%).The inhibitory potency of drugs was assessed by measuring reductions inthe peak amplitude of Na⁺ currents induced by increasing concentrationsof compounds tested. Na⁺ currents were elicited by stepping membranevoltage from holding potentials over the range −100 mV to −50 mV, to apulse potential of −10 mV. The test pulse duration was 5-10 msec,repeated at a frequency ≦1 Hz. Concentration-inhibition curves werefitted with equation 1:

I/I _(control)=1/(1+([compound]/IC ₅₀))  Eq. 1

where I_(control) is the maximal Na⁺ current in the absence ofantagonist, [compound] is the drug concentration, and IC₅₀ is theconcentration of compound that produces half maximal inhibition.

Binding Assay:

The ability of compounds of the present invention to modulate eithersite 1 or site 2 of the Na⁺ channel was determined following theprocedures fully described in Yasushi, J. Biol. Chem. 261:6149-6152(1986) and Creveling, Mol. Pharmacol. 23:350-358 (1983), respectively.Rat forebrain membranes were used as sources of Na⁺ channel proteins.The binding assays were conducted in 130 μM choline chloride at 37° C.for 60-minute incubation with [³H] saxitoxin and [³H] batrachotoxin asradioligands for site 1 and site 2, respectively.

The compounds of the present invention may be tested for in vivoanticonvulsant activity after iv or ip injection using a number ofanticonvulsant tests in mice (audiogenic seizure model in DBA-2 mice,pentylenetetrazol-induced seizures in mice, maximum electroshock seizuretest (MES)).

The compounds may be tested for their neuroprotective activity afterfocal and global ischemia produced in rats or gerbils according to theprocedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993))and Sheardown et al. (Eur. J. Pharmacol. 236:347-353 (1993)) and Grahamet al. (J. Pharmacol. Exp. Therap. 276:1-4 (1996)).

The compounds may be tested for their neuroprotective activity aftertraumatic spinal cord injury according to the procedures described inWrathall et. al. (Exp. Neurology 137:119-126 (1996)) and Iwasaki et. al.(J. Neuro Sci. 134:21-25 (1995)).

Compositions within the scope of this invention include all compositionswherein the compounds of the present invention are contained in anamount which is effective to achieve its intended purpose. Whileindividual needs vary, determination of optimal ranges of effectiveamounts of each component is within the skill of the art. Typically, thecompounds may be administered to mammals, e.g. humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the mammal beingtreated for epilepsy, neurodegenerative diseases, anesthesia,arrhythmia, manic depression, and pain. For intramuscular injection, thedose is generally about one-half of the oral dose.

In the method of treatment or prevention of neuronal loss in global andfocal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia,status epilepsy and surgery, the compound can be administrated byintravenous injection at a dose of about 0.025 to about 10 mg/kg.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound. The unit dose maybe administered one or more times daily as one or more tablets eachcontaining from about 0.1 to about 10, conveniently about 0.25 to 50 mgof the compound or its solvates.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the particular 2-aminoacetamide of the present invention with asolution of a pharmaceutically, acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticacid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalicacid, dichloroacetic acid, and the like. Basic salts are formed bymixing a solution of the particular 2-aminoacetamide of the presentinvention with a solution of a pharmaceutically acceptable non-toxicbase such as sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate and the like.

The pharmaceutical compositions of the invention may be administered toany animal which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humans,although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, or buccal routes.Alternatively, or concurrently, administration may be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetyl-cellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which can be used rectally include,for example, suppositories, which consist of a combination of one ormore of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include, aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances which increase the viscosity of the suspensioninclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

Example 1 2-(4-(2-Fluorobenzyloxy)benzylamino)-2-methyl-propanamide asNa⁺ channel blocker

2-(4-(2-Fluorobenzyloxy)benzylamino)-2-methyl-propanamide was tested inthe electrophysiological and binding assays described above and produceddose-dependent inhibition of voltage-gated Na⁺ currents recorded inacutely dissociated rat hippocampal neurons. The blocking effect of thiscompound on Na⁺ currents was highly sensitive to the holding voltage.For example, at concentrations between 0.1-10 μM,2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide had verylittle effect on Na⁺ currents activated from a holding membrane voltageof −100 mV, but inhibited currents with increasing potency as theholding potential was progressively depolarized. The most potent blockin these studies was seen at a membrane holding voltage of −65 mV. Thedecrease in current was due to steady-state inactivation of the Na⁺channels.

This data indicates that2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide binds tovoltage-sensitive Na⁺ channels in their inactivated states and has weakpotency towards Na⁺ channels in their resting states (Ragsdale et al.,Mal. Pharmacol. 40:756-765 (1991); Kuo and Bean, Mol. Pharmacol.46:716-725 (1994)). The apparent antagonist dissociation constant(K_(d)) of this compound for inactivated Na⁺ channels is ˜1.2 μM.

Example 22-(4-(3,4-Methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide

-   a) 4-(3,4-Methylenedioxyphenoxy)benzaldehyde: A mixture of sesamol    (5.13 g, 37.1 mmol), 4-fluorobenzaldehyde (4.0 mL, 37.3 mmol),    potassium carbonate (6.21 g, 44.9 mmol) in N,N-dimethylacetamide (50    mL) was refluxed for 23 h. The mixture was added to water and    extracted with an ethyl acetate/hexane solution. The organic layer    was washed with aqueous sodium hydroxide (2 N), dried over sodium    sulfate, and evaporated under reduced pressure to give crude    product. The crude product was purified by flash chromatography to    give a pink solid, which was decolorized by refluxing with activated    charcoal in chloroform for 1 h. Filtration through Celite and    removal of the chloroform in vacuo gave the desired aldehyde. ¹H NMR    (CDCl₃) δ 9.91 (s, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.03 (d, J=8.4 Hz,    2H), 6.82 (d, J=8.7 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.58-6.54 (m,    1H), 6.02 (s, 2H).-   b) 2-Amino-2,2-dimethylethanamide: A solution of HCl in dioxane (4.0    M), methanol (54 ml) and aminoisobutyric acid (11.7 g, 0.114 mol)    was refluxed for 6 h. Once at rt, the solution was concentrated to a    white solid. NMR of the solid showed that the solid was a mixture of    aminoisobutyric acid and methyl 2-amino-2,2-dimethylacetate. This    crude intermediate was heated to 50 degree Celsius in aqueous    ammonium hydroxide (29%, 140 ml) in a sealed tube for 24 hours. The    solution was cooled to room temperature, then evaporated under    reduced pressure to give a white solid. ¹H NMR of the solid showed    that the white solid contained 40% of the title product. ¹H NMR    (CDCl₃) δ 7.80 (s, 2H), 7.48 (s, 2H), 1.27 (s, 6H).-   c) 2-(4-(3,4-Methylenedioxyphenoxy)benzylamino)-2-methylpropanamide:    To a solution of 4-(3,4-methylenedioxyphenoxy)benzaldehyde (0.51 g,    0.21 mmol) in 30 mL of anhydrous ethanol was added 3 Å molecular    sieves (1 g), and 2-amino-2,2-dimethylethanamide (1.67 g, 40% by    weight by ¹H NMR, 0.49 mmol). After stirring for 24 h, the resulting    mixture was treated with sodium cyanoborohydride (95%; 1.0 g, 16    mmol). After stirring for an additional 8 h, the reaction was    quenched with water. The aqueous layer was extracted three times    with an ethyl acetate/hexane mixture. The combined organic layers    were dried over sodium sulfate and evaporated under reduced    pressure. The crude product was purified by column chromatography to    give 77 mg (11%) of the title product, mp=123-124° C. ¹H NMR (CDCl₃)    δ 7.25 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz,    1H), 6.55 (s, 1H), 6.47 (d, J=8.1 Hz, 1H), 5.96 (s, 2H), 5.47 (bs,    2H), 3.66 (s, 2H), 1.42 (s, 6H).

The following compounds were prepared similarly:

2-(4-(4-Fluorophenoxy)benzylamino)-2-methylpropanamide: mp=103-106° C.;¹H NMR (CDCl₃) δ 7.27 (d, J=8.4 Hz, 2H), 7.02-6.92 (m, 6H), 5.6 (bs,2H), 3.68 (s, 2H), 1.43 (s, 6H).

2-(4-(2,4-Difluorophenoxy)benzylamino)-2-methylpropanamide: TLC solvent:60:40 hexane/ethylacetate; TLC R_(f) 0.5; ¹H NMR (CDCl₃) δ 7.27-6.85 (m,7H), 5.5 (bs, 2H), 3.67 (s, 2H), 1.42 (s, 6H).

2-(4-(5-Indanoxy)benzylamino)-2-methylpropanamide: mp=81-83° C.; ¹H NMR(CDCl₃) δ 7.25 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 1H), 6.95 (d. J=8.4Hz, 2H), 6.87 (s, 1H), 6.78 (d, J=6.0 Hz, 1H), 5.5 (bs, 2H), 3.66 (s,2H), 2.88 (t, J=6.9 Hz, 4H), 2.19-2.0 (m, 2H), 1.41 (s, 6H).

The following compounds can be similarly prepared by allowing theappropriate aldehyde precursor to react with 2-methylpropanamide asdescribed above:

-   2-(4-(3,4-Methylenedioxyphenoxy)benzylamino)-2-methylpropanamide-   2-(4-Cyclohexyloxybenzylamino)-2-methylpropanamide-   2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methylpropanamide-   2-(4-(2-Adamantanoxy)benzylamino)-2-methylpropanamide-   2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(2-Chloro-4-fluorophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(3,4-Difluorophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(3,5-Difluorophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(6-Bromo-4-fluorophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(4-Nitrophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(4-Tetrahydropyranoxy)benzylamino)-2-methylpropanamide-   2-(4-(4-Chlorophenoxy)benzylamino)-2-methylpropanamide-   2-(4-(4-Methylphenoxy)benzylamino)-2-methylpropanamide-   2-(4-Cycloheptoxybenzylamino)-2-methylpropanamide-   2-(4-(1-Methyl-4-piperidinoxy)benzylamino)-2-methylpropanamide-   2-(4-(exo-2-norbornoxy)benzylamino)-2-methylpropanamide-   2-(3-(4-Fluorophenoxy)-5-pyridylmethylamino)-2-methylpropanamide-   2-(4-(4-Pyridinoxy)benzylamino)-2-methylpropanamide-   2-(3-Fluoro-4-(4-fluorophenyl)benzylamino)-2-methylpropanamide-   2-(4-(2-Pyrimidinoxy)benzylamino)-2-methylpropanamide-   2-(4-(6-Quinolinoxy)benzylamino)-2-methylpropanamide-   2-(4-(N,N-diphenylamino)benzylamino)-2-methylpropanamide-   2-(4-Diphenylmethoxy)benzylamino)-2-methylpropanamide-   2-(4-Triphenylmethoxy)benzylamino)-2-methylpropanamide-   2-(4-(3,4-Methylenedioxybenzyloxy)benzylamino)-2-methylpropanamide

The ability of selected 2-methylpropanamide derivatives to block maximalelectroshock-induced seizures (MES) was determined by the followingprocedure.

Seizures were induced by application of current (50 mA, 60 pulses/sec,0.8 msec pulse width, 1 sec duration, D.C.) using a Ugo Basile ECTdevice (model 7801). Mice were restrained by gripping the loose skin ontheir dorsal surface and saline-coated corneal electrodes were heldlightly against the two cornea. Current was applied and mice wereobserved for a period of up to 30 sec for the occurrence of a tonichindlimb extensor response. A tonic seizure was defined as a hindlimbextension in excess of 90 degrees from plane of the body. The2-methylpropanamides tested were administered iv to mice 10 min beforethe test procedure.

TABLE 1 Activity of Substituted Benzylamino 2-methylpropanamide in MESiv in mouse Example iv MES activity (number Substituent No.protected/number screened) 4-fluorophenoxy 2 8/83,4-methylenedioxyphenoxy 2 8/8 2,4-difluorophenoxy 2 8/8 5-indanoxy 21/8

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1. A method of treating or ameliorating pain in a mammal, comprisingadministering to a mammal in need of such treatment an effective amountof a compound having the Formula II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R₁,R₂, R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl orcarboxyalkyl; R₅, R₆ and R₇ are independently hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl,alkoxyalkyl or carboxyalkyl, or R₅, is defined as above, and R₆ and R₇together with the nitrogen atom to which they are attached form aheterocycle; A₁ and A₂ are independently aryl, heteroaryl, saturated orpartially unsaturated carbocycle or saturated or partially unsaturatedheterocycle, any of which is optionally substituted; X is one of O, S,NR₈, CH₂, C(O), NR₈C(O), C(O)NR₈, SO, SO₂ or a covalent bond; where R₈is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl,aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; and n is 0, 1, 2or
 3. 2-19. (canceled)